Chemokines which are the cell chemotactic factors are roughly classified into two types based on the structural characteristics, i.e., CXC/α chemokines and CC/β chemokines. Receptors of these chemokines belong to the 7-transmembrane G protein-coupled receptor family and are constituted by CXC chemokine receptors and CC chemokine receptors (Non-patent Reference 1).
CC chemokine receptor 4 (CCR4) was cloned from T lymphocyte and thymus (Non-patent Reference 2, Non-patent Reference 3) and reported to be expressed mainly in a T cell called Th2 type at the beginning (Non-patent Reference 4). However, it was shown by the detailed analyses thereafter that CCR4 is broadly present in the effector-memory T cells of Th1 and Th2 (Non-patent Reference 5, Non-patent Reference 6). According to further recent studies, it has been revealed that CCR4 is present in almost all of the skin-tropic T cells (Non-patent Reference 7) and monocyte, macrophage, dendritic cell and NK cell (Non-patent Reference 8).
Thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) as CC chemokines are specific ligands for CCR4 (Non-patent Reference 9, Non-patent Reference 10). The TARC was found as a T cell chemotactic factor (Non-patent Reference 11), and the MDC as a chemotactic factor of monocyte, macrophage and NK cell (Non-patent Reference 12). It is known that both of the chemokines have characteristics of both inflammatory chemokine and homeostatic chemokine (Non-patent Reference 13).
It has been suggested by a large number of reports that CCR4 and its ligands TARC and MDC are concerned in various diseases such as inflammatory diseases, allergic diseases, autoimmune diseases and the like. For example, asthma (Non-patent Reference 14), atopic dermatitis (Non-patent Reference 15), psoriasis (Non-patent Reference 16), rheumatoid arthritis (Non-patent Reference 17), inflammatory bowel disease (Non-patent Reference 18) and the like may be exemplified. Accordingly, an agent that modulates the functions of CCR4 is expected as an agent for preventing or treating these diseases and the like. As the agents for preventing or treating the above-mentioned inflammatory diseases, allergic diseases, autoimmune diseases and the like, various drugs such as steroid agents and the like are used. From the viewpoint of their therapeutic effects and side effects, great concern has been directed toward the development of a drug based on a new functional mechanism.
For example, it has been reported that a compound represented by the following formula has an activity to modulate the functions of TARC or MDC (Patent Reference 1).
[See said reference for symbols in the formula.]
Also, it has been reported that, for example, a compound represented by the following formula has an activity to modulate the functions of CCR4 (Patent Reference 2).
[See said reference for symbols in the formula.]
Also, it has been reported that a compound represented by the following formula has an activity to modulate the functions of CCR4 (Patent Reference 3).
[See said official gazette for symbols in the formula.]
Also, it has been reported that a compound represented by the following formula has an activity to modulate the functions of CCR4 (Patent Reference 4).
[See said reference for symbols in the formula.]
In addition, it has been reported that a compound represented by the following formula has the action to modulate function of CCR4 (Patent Reference 5).
[See said reference for symbols in the formula.]
However, there is no disclosure or suggestion in any one of the above-mentioned references on the acylaminopiperidine compound according to the present invention.
Non-patent Reference 1: Pharmacological Reviews, 52, 145, 2000
Non-patent Reference 2: Biochemical and Biophysical Research Communications, 218, 337, 1996
Non-patent Reference 3: European Journal of Immunology, 26, 3021, 1996
Non-patent Reference 4: Journal of Experimental Medicine, 187, 875, 1998
Non-patent Reference 5: Journal of Immunology, 166, 103, 2001
Non-patent Reference 6: The Journal of Clinical Investigation, 108, 1331, 2001
Non-patent Reference 7: Nature, 400, 776, 1999
Non-patent Reference 8: Arthritis & Rheumatism, 44, 1022, 2001
Non-patent Reference 9: Journal of Biological Chemistry, 272, 15036, 1997
Non-patent Reference 10: Journal of Biological Chemistry, 273, 1764, 1998
Non-patent Reference 11: Journal of Biological Chemistry, 271, 21514, 1996
Non-patent Reference 12: Journal of Experimental Medicine, 185, 1595, 1997
Non-patent Reference 13: Immunology Today, 20, 254, 1999
Non-patent Reference 14: The Journal of Clinical Investigation, 107, 1357, 2001
Non-patent Reference 15: Journal of Investigative Dermatology, 115, 640, 2000
Non-patent Reference 16: Laboratory Investigation, 81, 335, 2001
Non-patent Reference 17: Arthritis & Rheumatism, 44, 2750, 2001
Non-patent Reference 18: Clinical & Experimental Immunology, 132, 332, 2003
Patent Reference 1: International Publication WO 03/104230
Patent Reference 2: US Patent Publication 2004/0048865
Patent Reference 3: International Publication WO 2005/082865
Patent Reference 4 International Publication WO 2005/085212
Patent Reference 5: International Publication WO 2005/123697